"Protein protein interaction directed libraries"

描述(由申请人提供)：P41拨款提案(用于高通量筛选的试点规模图书馆(PSL))题为“蛋白质相互作用导向的化合物文库”，将基于56个支架产生1,760个化合物，旨在(ANT-)刺激蛋白质相互作用(PPI)。 众所周知，PPI界面--尽管不容易归类--没有随机的氨基酸分布。事实上，许多PPI的Phe、Trp和Leu含量都高于平均水平，这些都是PPI界面中心最丰富的氨基酸。这些锚定残基经常在界面上被深度匆忙，并贡献了两个蛋白质相互作用的大部分能量。那些具有重要能量的地点通常被称为“热点”。基于我们对许多含有Trp、Phe和Leu片段的PPI界面的深入分析，我们在这里提出了含有Trp、Phe和Leu片段的小分子文库应该比通常的筛选文库具有更大的(ANT-)PPI激动率。这也是基于我们最近成功地找到了与癌症相关的PPI、P53/MDM2和P53/MDM4的非常有效的拮抗剂，其中我们在拮抗剂的设计中使用Trp作为中心锚定片段。本文合成的化合物将通过可能靶向蛋白质相互作用来补充目前MLSMR的筛选文库。蛋白质相互作用涉及所有与疾病相关的途径，对于未来设计新药来解决未得到满足的医疗需求，如糖尿病、癌症和阿尔茨海默病，了解这些相互作用是极其重要的。 与公共健康相关：该提案通过提供旨在(ANT-)刺激蛋白质相互作用的化合物来解决RFA问题。这些图书馆很可能会导致新的生物模式，并导致进一步的后续项目，旨在解开它们的行动模式。这些化合物具有高分析质量、新颖、多样化和生物灵感。

DESCRIPTION (provided by applicant): The P41 grant proposal (Pilot-Scale Libraries (PSL) for High-Throughput Screening) titled "Protein protein interaction directed compound libraries" will produce 1,760 compounds based on 56 scaffolds aiming to (ant-) agonize protein protein interaction (PPI). It is well established that PPI interfaces - although not easily to categorize - do not have random amino acid distribution. In fact many PPIs have a higher than average Phe, Trp and Leu content and these are the most abundant amino acids in the center of PPI interfaces. These anchor residues are often deeply hurried in the interfaces and contribute much of the energy of interaction of the two proteins. Those energetically important sites are often called "hot-spot". Based on our in depth analysis of many PPI Interfaces containing Trp, Phe and Leu we herein propose that small molecule libraries containing Trp,Phe and Leu fragments should have a much larger probability to (ant-)agonize PPIs than usual screening libraries. This is also based on our recent success of finding very potent antagonists for the cancer relevant PPI p53/mdm2 and p53/mdm4 where we used Trp as a central anchor fragment in the design of antagonists. The herein synthesized compounds will complement current screening libraries of the MLSMR by likely targeting protein protein interactions. Protein interactions are involved in all disease relevant pathways and are of uttermost importance to understand for the future design of novel drugs to address unmet medical needs, such as diabetes, cancer and Alzheimer's disease. PUBLIC HEALTH RELEVANCE: The proposal addresses the RFA by providing compounds which are designed to (ant-)agonize protein protein interaction. The libraries most likely will result in novel biological patterns and lead to further follow on projects aiming to deconvolute their mode-of-actions. The compounds are of high analytical quality, novel, diverse and biologically inspired.